This invention relates to a novel compound having a chemical structure which is different from those of the conventionally used antitumor agents, to an antitumor agent which contains the compound as its active ingredient and to a highly effective antitumor agent capable of showing its efficacy even against 5-FU drug resistant tumors.
Though a number of 5-FU drugs are currently used as antitumor agents which can be orally administered, it cannot be said that their effects are sufficient, and there are tumors which show resistance against 5-FU drugs, so that concern has been directed toward the development of a drug which has more higher effects and shows its efficacy even against 5-FU drug resistant tumors. In this connection, antitumor effects of pyrazole derivatives related to this invention are described in JP-A-9-48776 (the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d) and WO 98/32739. This invention is to provide pyrazole derivatives having a novel structure in which a condensed tricyclic heterocyclic ring is substituted, and this invention is also to provide novel compounds in which novel substituents are introduced into the pyrimidinyl group of JP-A-9-48776 and the cycloalkyl group, phenyl group, monocyclic heterocyclic ring group and the like of WO 98/32739.
It is to provide a highly effective antitumor agent which has a novel chemical structure different from that of the conventional antitumor agents and shows its efficacy even against 5-FU drug resistant tumors.
As a result of intensive investigations, the present inventors have found that a pyrazole derivative having a novel structure shows its efficacy even against 5-FU drug resistant tumors and has strong antitumor effects.
This invention has been accomplished by founding that this compound also exerts its effect upon P-glycoprotein expression multi-drug resistant strains which are causing clinical problems.
This invention relates to a compound represented by formula (I): 
[in the formula,
R1 represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, wherein the alkyl group may have a substituent selected from a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group and an alkylthio group;
R2 represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, an aryl group, an alkyl group or a cycloalkyl group, wherein the alkyl group and the cycloalkyl group may have a substituent selected from a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group and an alkylthio group;
R3 represents a hydrogen atom, a halogen atom, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, wherein the alkyl group may have a substituent selected from a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group and an alkylthio group;
R4 represents a hydrogen atom, a halogen atom, an alkoxyl group, an amino group, an alkylamino group, an aryl group or an alkyl group, wherein the alkyl group may have a substituent selected from a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group;
R5 represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an arylalkyl group, wherein the alkyl group may have a substituent selected from a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group and an alkylthio group;
Q represents an amidino group, a cycloalkyl group, a phenyl group or a monocyclic heterocyclic ring group, wherein these amidino group, cycloalkyl group, phenyl group and monocyclic heterocyclic ring group may have one or more substituents selected from the group consisting of an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), a halogen atom, a hydroxyl group, an alkoxyl group, an alkoxylalkoxyl group, an amino group, an alkylamino group, an acylamino group, an alkylaminoalkylamino group, a nitro group, a cyano group, a carbamoyl group, a thiol group, an alkylthio group, an arylthio group, an alkylsulfinyl group, an arylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, an aminosulfonyl group, an alkylaminosulfonyl group, an arylaminosulfonyl group and an aryl group; and
G represents a condensed tricyclic heterocyclic ring, wherein the condensed tricyclic heterocyclic ring may have one or more substituents selected from the group consisting of an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), a halogen atom, a hydroxyl group, an alkoxyl group, a thiol group, an alkylthio group, an amino group, an alkylamino group, an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group, the condensed tricyclic heterocyclic ring may have an epoxy group, and the condensed tricyclic heterocyclic ring may also have a carbonyl, group as a constituent element of the ring] or a salt thereof (with the proviso that, in this compound and a salt thereof, a compound [in which G is a condensed tricyclic heterocyclic ring, and a saturated or unsaturated hydrocarbon ring or heterocyclic ring of the condensed ring can be represented by a saturated hydrocarbon ring or saturated heterocyclic ring having no substituent (excluding a case in which Q is a pyrimidinyl group and binds at the 2-position)] and a salt thereof are excluded).
This invention also provides a compound represented by formula (Ia): 
[in the formula,
R1, R2, R3, R4, R5 and Q are as defined in the foregoing, and
G1 represents a condensed tricyclic heterocyclic group wherein the condensed tricyclic heterocyclic group comprises a nitrogen-containing heterocyclic ring, a saturated or unsaturated hydrocarbon ring or heterocyclic ring, and a benzene ring, wherein
the nitrogen-containing heterocyclic ring constituting the condense tricyclic heterocyclic ring may have one or more substituents selected from the group consisting of an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), a halogen atom, a hydroxyl group, an alkoxyl group, a thiol group, an alkylthio group, an amino group an alkylamino group, an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group, and the nitrogen containing heterocyclic ring may contain a carbonyl group as a constituent element of the ring,
the saturated or unsaturated hydrocarbon ring or heterocyclic ring constituting the condensed tricyclic heterocyclic ring may have one or more substituents selected from the group consisting of an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), an halogen atom, a hydroxyl group, an alkoxyl group, thiol group, an alkylthio group, an amino group, an alkylamino group, an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group, it may have an epoxy group between ring-forming two atoms, and the saturated or unsaturated hydrocarbon ring or heterocyclic ring may contain a carbonyl group as a constituent element of the ring, and
the benzene ring constituting the condensed tricyclic heterocyclic ring may have one or more substituents selected from the group consisting of an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), a halogen atom, a hydroxyl group, an alkoxyl group a thiol group, an alkylthio group, an amino group, an alkylamino group, an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group] or a salt thereof (with the proviso that, in this compound and a salt thereof, a compound [in which G1 is a condensed tricyclic heterocyclic ring, and a saturated or unsaturated hydrocarbon ring or heterocyclic ring of the condensed ring can be represented by a saturated hydrocarbon ring or saturated heterocyclic ring having no substituen (excluding a case in which Q is a pyrimidinyl group and binds at the 2-position)] and a salt thereof are excluded).
Among compounds represented by the aforementioned formula (I) or (Ia), a compound in which Q is a pyrimidinyl group and binds to the pyrazole ring at the 2-position and a salt thereof are preferable.
Also, among compounds represented by the aforementioned formula (I) or (Ia), a compound in which the saturated or unsaturated hydrocarbon ring or heterocyclic ring which constitutes the condensed tricyclic heterocyclic ring has a substituent and a salt thereof are preferable.
This invention also relates to a compound represented by formula (Ib): 
{in the formula,
R1, R2, R3, R4 and R5 are as defined in the foregoing,
G2 represents a group xe2x80x94Z1xe2x80x94Z2 
[wherein Z1 represents a nitrogen-containing saturated heterocyclic ring structure represented by 
(X is a nitrogen atom or CH), which may contain a ketone moiety, and the ring may have one or more groups as substituents selected from the group consisting of an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group and an aryl group, and
Z2 represents a phenyl group or a heterocyclic ring group, and these phenyl group an d heterocyclic ring group may have one or more substituents selected from the group consisting of an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group) a halogen atom, a hydroxyl group, an alkoxyl group, a thiol group, an alkylthio group an amino group, an alkylamino group, an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group]
or represents a condensed tricyclic heterocyclic ring group wherein the condensed tricyclic heterocyclic ring group may have one or more substituents selected from the group consisting of an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), a halogen atom, a hydroxyl group, an alkoxyl group, a thiol group, an alkylthio group, an amino group, an alkylamino group, an acylamino group, a nitro group, a cyano group, a carbamoyl group and an aryl group, the condensed tricyclic heterocyclic ring group may have an epoxy group, and the condensed tricyclic heterocyclic ring may contain a carbonyl group as a constituent element of the ring, and
Q1 represents a cycloalkyl group, a phenyl group or a monocyclic heterocyclic ring group, and these cycloalkyl group, phenyl group and monocyclic heterocyclic ring group may have at least one group selected from the following (A) and one or more groups selected from (B) as substituents,
(A) an alkyl group having a substituent (the substituent of alkyl group is a group selected from a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group and an arylsulfamoyl group, and it may further have at least one group selected from these groups),
a group xe2x80x94R71xe2x80x94R7 [R7 represents a monocyclic nitrogen-containing heterocyclic ring group or a cycloalkyl group, R71 represents single bond or an alkylene group having from 1 to 3 carbon atoms, and R7 and R71 (excluding the case of single bond) may each independently have one or more substituents selected from the group consisting of an alkyl group (which may have one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureidol group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group), a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group],
a group xe2x80x94R72xe2x80x94R73xe2x80x94R74xe2x80x94R7 [R7 represents a monocyclic nitrogen-containing heterocyclic ring group or a cycloalkyl group, each of R72 and R74 independently represents single bond or an alkylene group having from 1 to 3 carbon atoms, R73 represents an oxygen atom or a sulfur atom, and R7, R72 (excluding the case of single bond) and R74 (excluding the case of single bond) may each independently have one or more substituents selected from the group consisting of an alkyl group (which may have one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group), a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, analkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group],
a group xe2x80x94R72xe2x80x94NR75xe2x80x94R74xe2x80x94R8 [R72 and R74 each independently represents single bond or an alkylene group having from 1 to 3 carbon atoms, R75 represents an alkyl group (which may have one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group), a hydrogen atom, a hydroxyl group, an alkoxyl group or xe2x80x94R74xe2x80x94R8 and R8 represents an alkylsulfonyl group, an arylsulfonyl group, aminocyclic nitrogen-containing heterocyclic ring group or a cycloalkyl group, wherein R8 (excluding the case of alkylsulfonyl group and arylsulfonyl group), R72 (excluding the case of single bond) and R74 (excluding the case of single bond) may each independently have one or more substituents selected from the group consisting of an alkyl group (which may have one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group), a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group],
a group xe2x80x94R81xe2x80x94R82xe2x80x94R9 [R81 represents single bond or an alkylene group having from 1 to 3 carbon atoms, R82 represents an oxygen atom or a sulfur atom, wherein R81 (excluding the case of single bond) may have one or more substituents selected from the group consisting of alkyl group (which may have one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group) , a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group, and R9 represents an alkyl group having a substituent, wherein the substituent of alkyl group is selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group, and it may further have at least one group selected from these groups], or
a group xe2x80x94R81xe2x80x94NR83xe2x80x94R9 [R81 represents single bond or an alkylene group having from 1 to 3 carbon atoms, wherein R81 (excluding the case of single bond) may have one or more substituents selected from the group consisting of an alkyl group (which may have one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group), a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group, R83 represents an alkyl group (which may have one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group), a hydrogen atom, a hydroxyl group or an alkoxyl group, and R9 represents an alkyl group having a substituent, wherein the substituent of alkyl group is selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group, and it may further have at least one group selected from these groups (with the proviso that a case in which R81 is single bond, R83 is a hydrogen atom and R9 is an alkylamino group is excluded)],
(B) alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), a halogen atom, a hydroxyl group, an alkoxyl group, an alkoxylalkoxyl group, an amino group, an alkylamino group, an acylamino group, an alkylaminoalkylamino group, a nitro group, a cyano group, a carbamoyl group, a thiol group, an alkylthio group, an arylthio group, an alkylsulfinyl group, an arylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, an aminosulfonyl group, an alkylaminosulfonyl group, an arylaminosulfonyl group or an aryl group} or a salt thereof.
In this connection, those in which the double bond moiety of alkenyl group is either in cis form or trans form are included in the compounds of this invention represented by the formula (I), (Ia) or (Ib).
Also, these compounds of this invention include optional stereoisomers.
Next, the terms as used herein are described.
The xe2x80x9ccis (form)xe2x80x9d means a case in which R3 and R4 are bonded on the same side based on the double bond, and the xe2x80x9ctrans (form)xe2x80x9d means a case in which R3 and R4 are bonded on the opposite sides based on the double bond.
The xe2x80x9chydroxyl groupxe2x80x9d may be protected with a protective group.
The xe2x80x9camino groupxe2x80x9d may be protected with a protective group.
Unless otherwise noted, the xe2x80x9calkyl groupxe2x80x9d, xe2x80x9calkenyl groupxe2x80x9d and xe2x80x9calkynyl groupxe2x80x9d may be either straight chain or branched chain, and a group having from 1 (2 in the case of alkenyl group and alkynyl group) to 6 carbon atoms is desirable.
Alkyl moiety of the xe2x80x9calkoxyl groupxe2x80x9d has preferably from 1 to 6 carbon atoms.
The xe2x80x9caryl groupxe2x80x9d means a monovalent group formed by removing one hydrogen atom from an aromatic hydrocarbon nucleus, e.g., phenyl, tolyl, biphenylyl, naphthyl and the like.
Amino group of the xe2x80x9caminoalkyl groupxe2x80x9d may be bonded to any position of an alkyl group. Also, the alkyl group has preferably from 1 to 6 carbon atoms.
The xe2x80x9calkylamino groupxe2x80x9d means a group in which amino group is substituted by one alkyl group or amino group is substituted by two alkyl groups (the two alkyl groups may be the same or different from each other). Also, the alkyl group has preferably from 1 to 6 carbon atoms.
The xe2x80x9calkylureido groupxe2x80x9d means a group in which ureido group is substituted by one alkyl group or ureido group is substituted by two alkyl groups (the two alkyl groups may be the same or different from each other). Also, the alkyl group has preferably from 1 to 6 carbon atoms.
The xe2x80x9cacyl groupxe2x80x9d means a group in which hydrogen atom, an alkyl group or an aryl group is bonded to carbonyl group (xe2x80x94COxe2x80x94), e.g., formyl, acetyl, propanoyl, benzoyl and the like. In this case, a group having from 1 to 6 carbon atoms is desirable as the alkyl group to be bonded, and phenyl group is desirable as the aryl group to be bonded.
The xe2x80x9cheterocyclic ring groupxe2x80x9d means a group derived from a monocyclic or bicyclic saturated or unsaturated heterocyclic ring compound, and it contains one or more of at least one kind of atom selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom as a constituent atom of the ring. For example, groups derived from aziridine, azetidine, pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, pyrazine, triazine, piperazine, dioxane, pyran, morpholine, thiomorpholine and the like monocyclic heterocyclic ring compounds can be exemplified as the monocyclic heterocyclic ring group. Groups derived from benzofuran, indolizine, benzothiophene, indole, naphthyridine, quinoxaline, quinazoline, chroman and the like bicyclic heterocyclic ring compounds can be exemplified as the bicyclic heterocyclic ring group.
The xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d means a saturated or unsaturated heterocyclic ring which necessarily contains one nitrogen atom as a constituent atom of the heterocyclic ring, and it may further contain one or more of at least one atom selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom as constituent atoms, e.g., aziridine, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, homopiperazine, tetrahydropyridine, morpholine, thiomorpholine, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like.
The xe2x80x9cnitrogen-containing heterocyclic ring groupxe2x80x9d means a group derived from the above xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d.
The xe2x80x9cnitrogen-containing saturated heterocyclic ringxe2x80x9d means a saturated group among the above xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d.
The xe2x80x9ccondensed tricyclic heterocyclic ring groupxe2x80x9d means a condensed ring group composed of three rings containing at least one heterocyclic ring. As the condensed tricyclic heterocyclic ring group, a group derived from an ortho condensation compound is desirable. The ortho condensation means a structure in which two rings constituting a polycyclic compound have only two common atoms, and one or more common planes and common atoms two times the number of common planes are present in such a type of compound.
The xe2x80x9csingle bondxe2x80x9d means a simple bond; for example, when R71 of xe2x80x94R71xe2x80x94R7 is single bond, R71 does not substantially exist and the entire structure becomes xe2x80x94R7.
When described herein as xe2x80x9chas a substituentxe2x80x9d or xe2x80x9cmay have a substituentxe2x80x9d, binding position of the substituent is not particularly limited.
Next, each substituent of the compound represented by the formula (I), (Ia) or (Ib) (to be referred also to as xe2x80x9ccompound (I), (Ia) or (Ib) of this inventionxe2x80x9d hereinafter, the same is applied to other formulae) is described.
R1 is preferably a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, a phenyl group or an alkyl group, and the alkyl group may have an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group as a substituent.
R2 is preferably a hydroxyl group, an alkoxyl group, an amino group, an alkyl group or a cycloalkyl group, and the alkyl group and cycloalkyl group may have a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group as a substituent.
R3 is preferably a hydrogen atom or an alkyl group, and the alkyl group may have an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group as a substituent.
R4 is preferably a hydrogen atom or an alkyl group, and the alkyl group may have an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group as a substituent.
R5 is preferably a hydrogen atom or an alkyl group, and the alkyl group may have an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group as a substituent.
G represents a condensed tricyclic heterocyclic ring group. Though it should not particularly be limited, a group composed of a nitrogen-containing heterocyclic ring, a saturated or unsaturated hydrocarbon ring or heterocyclic ring and benzene ring is desirable as the condensed tricyclic heterocyclic ring group.
Also, G may or may not have a substituent but preferably have a substituent.
Regarding the condensed tricyclic heterocyclic ring group G, constituent elements of G1 of the compound (Ia) of this invention are limited to a nitrogen-containing heterocyclic ring,a saturated or unsaturated hydrocarbon ring or heterocyclic ring and benzene ring.
The nitrogen-containing heterocyclic ring which constitutes G1 may or may not have a substituent but preferably have a substituent. Those which will be described later can be exemplified as such a substituent.
Next, G2 of the compound (Ib) of this invention is described.
In the case of the group xe2x80x94Z1xe2x80x94Z2, the nitrogen-containing saturated heterocyclic ring structure Z1 represented by formula: 
(in the formula, X represents a nitrogen atom or CH) is preferably a group which has a size of five- or six-membered ring, and a group derived from piperazine or piperidine is particularly desirable.
Regarding the heterocyclic ring group of Z2, a monocyclic group having a size of five- or six-membered ring is preferable, and an unsaturated one is more preferable. Illustratively, a pyridyl group, a pyridazyl group, a pyrazyl group, a pyrimidyl group or a triazyl group is desirable.
A phenyrl group or a pyrimidinyl group is desirable as Z2. The phenyl group and pyrimidinyl group may have a substituent, and a case having the same or different two substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group and an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group) is desirable.
As the Z2, a phenyl group having the same or different two substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group and an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group) is most desirable.
When G2 is a condensed tricyclic heterocyclic ring group, a group composed of a nitrogen-containing heterocyclic ring, a saturated or unsaturated hydrocarbon ring or heterocyclic ring and benzene ring is desirable as the condensed tricyclic heterocyclic ring group.
It is desirable that the condensed tricyclic heterocyclic ring group of G, G1 or G2 has the nitrogen atom of a nitrogen-containing heterocyclic ring which constitutes the condensed tricyclic heterocyclic ring group, as a free valency.
As the nitrogen-containing heterocyclic ring which constitutes the condensed tricyclic heterocyclic ring group of G, G1 or G2 a size of six-membered ring is desirable, illustratively, piperazine, piperidine and tetrahydropyridine are desirable. In addition, those in which the piperazine, piperidine and tetrahydropyridine rings contain carbonyl group as a constituent element can also be cited as preferable examples.
As the saturated or unsaturated hydrocarbon ring or heterocyclic ring which constitutes the condensed tricyclic heterocyclic ring group of G, G1 or G2, a size of from five- to seven-membered ring is desirable, and a six-membered ring is particularly desirable. In addition, those which contain carbonyl group as a constituent element of the rings can also be cited as preferable examples.
As illustrative structure of the condensed tricyclic heterocyclic ring group of G, G1 or G2, a ring represented by 
wherein X1 represents an oxygen atom, a sulfur atom, NH, CH2 or Cxe2x95x90O, each of m and n is independently 0 or an integer of 1 or 2, and the partial structure represented by 
may form an unsaturated ring by containing a double bond, wherein X1 becomes N or CH when the carbon atoms adjacent to X1 form a double bond) is desirable.
Regarding the structure represented by 
the following can be cited as its illustrative examples. 
Among these illustrative examples, the following structures are desirable. 
As the substituent of the nitrogen-containing heterocyclic ring moiety which constitutes the condensed tricyclic heterocyclic ring group of G, G1 or G2, an alkyl group (which may be substituted by a halogen atom, an amino group, an alkylamino group, a hydroxyl group, an alkoxyl group, a thiol group or an alkylthio group), a hydroxyl group, an alkoxyl group and an amino group are desirable.
As the substituent of the saturated or unsaturated hydrocarbon ring moiety or heterocyclic ring moiety which constitutes the condensed tricyclic heterocyclic ring group of G, G1 or G2, an alkyl group (which may be substituted by an amino group, an alkylamino group, a hydroxyl group or an alkoxyl group), a hydroxyl group, an alkoxyl group, an amino group and an alkylamino group are desirable.
In addition, a case having an epoxy group between the ring-forming two carbon atoms is also desirable.
As the substituent of the benzene ring which constitutes the condensed tricyclic heterocyclic ring group of G, G1 or G2, an alkyl group (which may be substituted by an amino group, an alkylamino group, a hydroxyl group or an alkoxyl group), a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group and a cyano group are desirable.
Regarding m and n, a case in which the total of m and n becomes 0, 1 or 2 is desirable, and a case in which it becomes 1 is particularly desirable.
Q or Q1 is preferably a monocyclic heterocyclic ring group.
The monocyclic heterocyclic ring group of Q or Q1 is preferably an unsaturated group, more preferably a group having a size of five- or six-membered ring.
Most preferred as the monocyclic heterocyclic ring group of Q or Q1 is a nitrogen-containing heterocyclic ring group which is an unsaturated monocyclic heterocyclic ring group having a size of five- or six-membered ring and containing at least one nitrogen atom as a constituent atom of the heterocyclic ring and, illustratively, those which are derived from pyridine, pyrimidine, pyridazine, pyrazine and triazine are desirable. However, when Q is pyrimidine, a compound and salts thereof, in which G or G1 is a condensed tricyclic heterocyclic ring and a saturated or unsaturated hydrocarbon ring or heterocyclic ring of the condensed ring can be represented by a saturated hydrocarbon ring or saturated heterocyclic ring having no a substituent (excluding a case in which Q is a pyrimidinyl group and binds at the 2-position), are excluded from the compound (I) and (Ia) of this invention.
Q1 always has at least one substituent selected from (A) and may also have a substituent selected from (B). Among (B), an alkyl group, an amino group, an alkylamino group, a hydroxyl group or an alkoxyl group is desirable, and the alkyl group may have one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trialkylammonio group, a cyano group, an ureido group, an alkylureido group, an amidino group, a guanidino group, an alkoxyl group, a hydroxyalkoxyl group, an alkoxylalkoxyl group, an aminoalkoxyl group, a hydroxyalkylamino group, an aminoalkylamino group, a carboxyl group, a carbamoyl group, a sulfamoyl group, an alkylsulfamoyl group, an arylsulfamoyl group, a thiol group and an alkylthio group.
As the compound (I), (Ia) or (Ib) of this invention, its trans form (a case in which R3and R4 are bonded on the opposite sides based on the double bond) is desirable.
The compound (I) of this invention can be produced by various methods, and a typical production example is shown below. 
(R1, R2, R4, Q and G are as defined in the foregoing.)
That is, the compound (I) of interest can be obtained by reducing a compound (III) obtained by subjecting a compound (II) and a basic compound H-G to Mannich reaction, thereby converting it into a compound (IV), and subsequently dehydrating the product.
Each reaction is described in detail. Mannich reaction:
The compound (III) can be obtained by treating the compound (II) and basic compound H-G in a solvent in the presence of a condensing agent. It is desirable to use the basic compound H-G as its hydrochloride, hydrobromide or the like salt.
As the condensing agent, p-formaldehyde, formaldehyde and the like can be exemplified.
Examples of the solvent to be used include methanol, ethanol, propanol or the like alcohol solvent, N,N-dimethylformaide, acetamide, dimethylacetamide or the like amide solvent, chloroform, dichloromethane, carbon tetrachloride or the like halogenated hydrocarbon solvent, diethyl ether, tetrahydrofuran, dioxane or the like ether solvent and benzene, toluene, xylene or the like aromatic hydrocarbon solvent. A mixed solvent thereof may also be used.
The reaction temperature may be generally within the range of from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably within the range of from 0xc2x0 C. to 100xc2x0 C.
The reaction period may be generally within the range of from 5 minutes to 120 hours, preferably within the range of from 30 minutes to 72 hours.
Reduction Reaction
The corresponding compound (IV) can be obtained by reducing the compound (III).
The reduction can be carried out by a method generally used in this field. For example, a method in which the compound is treated in the presence of a reducing agent or a method in which hydrogenation is carried out in the presence of a catalyst can be cited.
Example s of the reducing agent include boron hydride compounds and aluminum hydride compounds, such as sodium borohydride, sodium cyanoborohydride and lithium aluminum hydride. Also, palladium, Raney nickel, platinum oxide and the like can be exemplified as the catalyst.
The solvent to be used is optionally selected depending on the reducing agent, and its examples include methanol, ethanol, propanol or the like alcohol solvent, N,N-dimethylformamide, acetamide, dimethylacetamide or the like amide solvent, chloroform, dichloromethane, carbon tetrachloride or the like halogenated hydrocarbon solvent, diethyl ether, tetrahydrofuran, dioxane or the like ether solvent and benzene, toluene, xylene or the like aromatic hydrocarbon solvent. A mixed solvent there of may also be used.
The reaction temperature may be generally within the range of from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably within the range of from 0xc2x0 C. to 100xc2x0 C.
The reaction period may be generally within the range of from 5 minutes to 72 hours, preferably within the range of from 10 minutes to 24 hours.
Dehydration Reaction
The compound (I) of interest can be obtained by subjecting the compound (IV) to dehydration reaction.
The dehydration can be carried out by a method generally used in this field, and a method in which heating is carried out in the presence of an acid can be exemplified.
The acid which can be used in this method may be either an organic acid or an inorganic acid. Hydrochloric acid, sulfuric acid, hydrobromic acid, potassium hydrogensulfate and the like can be exemplified as the inorganic acid, and p-toluenesulfnic acid, methanesulfonic acid, oxalic acid and the like can be exemplified as the organic acid. The inorganic acid is prefer ably used. Also, alumina may be used.
The reaction may be carried out using a solvent, and its examples include N,N-dimethylformamide, acetamide, dimethylacetamide or the like amide solvent, chloroform, dichloromethane, carbon tetrachloride or the like halogenated hydrocarbon solvent, diethyl ether, tetrahydrofuran, dioxane or the like ether solvent and benzene, toluene, xylene or the like aromatic hydrocarbon solvent. A mixed solvent thereof may also be used.
The reaction temperature may be generally within the range of from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably within the range of from 0xc2x0 C. to 100xc2x0 C.
The reaction period may be generally within the range of from 5 minutes to 72 hours, preferably within the range of from 10 minutes to 24 hours.
A compound in which R3 is a hydrogen atom and the alkenyl group moiety is trans form can be synthesized by the synthesis method shown in the above, and a compound in which R3 is an alkyl group and a compound in which the alkenyl group moiety is cis form can be synthesized by the following method. 
(A represents a chlorine atom, a bromine atom or an iodine atom, and R1, R2, R3, R4, R5, Q and G are as defined in the foregoing.)
That is, a compound represented by the formula (I) can be obtained by subjecting a compound (IIa) and a compound (V) to Witting reaction.
The production method shown by the above drawing is described in detail.
The compound (I) can be obtained by allowing the compound (V) to react with a tertiary phosphine in a solvent, treating the thus obtained phosphonium salt with a base in a solvent and then adding the compound (IIa).
As the tertiary phosphine to be used, triphenylphosphine, tri-n-butylphosphine and the like can be exemplified.
Examples of the base include n-butyl lithium, phenyl lithium, sodium hydride, potassium t-butoxide, sodium ethoxide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
Examples of the solvent which can be used include diethyl ether, tetrahydrofuran, dioxane or the like ether solvent, benzene, toluene, xylene or the like aromatic hydrocarbon solvent, methanol, ethanol, propanol or the like alcohol solvent, N,N-dimethylformamide, acetamide, dimethylacetamide or the like amide solvent and chloroform, dichloromethane, carbon tetrachloride or the like halogenated hydrocarbon solvent. A mixed solvent thereof may also be used.
The reaction temperature may be generally within the range of from 30xc2x0 C. to 150xc2x0 C., preferably within the range of from 50xc2x0 C. to 100xc2x0 C.
The reaction period may be generally within the range of from 5 minutes to 72 hours, preferably within the range of from 10 minutes to 24 hours.
According to the aforementioned production method of the compound (I) of this invention, a compound (Ia) of this invention can be produced in the same manner by the use of the basic compound H-G and compound (V), in which G1 is substituted instead of G. Also, a compound (Ib) of this invention can be produced in the same manner as the case of the aforementioned compound (I) of this invention, by the use of the compound (II) and compound (IIa), in which Q is changed to Q1, and the basic compound H-C and compound (V), in which G2 is substituted instead of G.
The compound (II) and compound (IIa) and the basic compound H-C and compound (V) , as the material compounds, are known compounds or compounds which can be easily synthesized in accordance with known methods described, for example, in JP-A-9-48776, JP-B-54-17760 (the term xe2x80x9cJP-Bxe2x80x9d as used herein means an xe2x80x9cexamined Japanese patent publicationxe2x80x9d), JP-B-50-5198, JP-A-8-269057, JP-A-6-279442, JP-W-9-504789 (the term xe2x80x9cJP-Wxe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese international patent applicationxe2x80x9d), JP-A-50-58234, JP-A-52-83397, JP-B-46-33032, Indian Journal of Chemistry, vol. 13, p. 462 (1975), Indian Journal of Chemistry, Sect. B, 25B (12), pp. 1231-1233 (1986), Indian Journal of Chemistry, Sect. B, 17B (3), pp. 244-245 (1979), Journal of Medicinal Chemistry, vol. 13, p. 516 (1970), Indian Journal of Chemistry, vol. 7, p. 833 (1969 ), Helvetica Hemica Acta, vol. 20, p. 1388 (1937), WO 98/00134, WO 98/00401, U.S. Pat. No. 4,367,335, German Patent No. 1901262, Swiss Patent No. 500213 and the like, or by methods which can be generally used by those skilled in the art with reference to these documents.
In addition, the compound (I) of interest can also be obtained in the following manner via an allylation and then via a reductive amination or a substitution reaction. Also, the compound (Ia) of this invention can be produced in the same manner as the case of the aforementioned compound (I) of this invention by the use of the basic compound H-G in which G is replaced by G1, and the compound (Ib) of this invention can be produced in the same manner as the case of the aforementioned compound (I) of this invention by the use of the compound (IIa) in which Q is changed to Q1 and the basic compound H-G in which G2 is substituted instead of G. 
(M represents a metal such as an alkali metal, an alkaline earth metal, tin, zinc or nickel, R represents a protective group of the hydroxyl group, and R1, R2, R3, R5, Q and G are as defined in the foregoing.)
That is, the hydroxyl group of a compound (VI) obtained by allowing the compound (IIa) to react with an appropriate allyl metal compound or to undergo addition reaction with an allyl silane in the presence of a Lewis acid is protected to obtain a compound (VII) which is then oxidized to obtain a compound (VIII). The thus obtained compound (VIII) and a basic compound H-G are subjected to reductive amination, deprotected as occasion demand and then subjected to dehydration reaction, thereby obtaining the compound (I). Alternatively, it is possible to obtain the compound (X) by subjecting the compound (VIII) to a reduction reaction or allowing it to react with an alkyl metal compound, thereby converting it into a compound (IX), further converting its hydroxyl group into a leaving group and then carrying out substitution reaction with a basic compound H-G.
Each reaction step is described.
Addition Reaction
The compound (VI) can be obtained by, in a solvent, allowing the compound (IIa) to react with an appropriate allyl metal compound or to undergo addition reaction with an allyl silane in the presence of a Lewis acid (titanium tetrachloride or the like).
Examples of the allyl metal compound which can be used in the reaction include allyl lithium, allyl magnesium halide and allyl tin compound.
Examples of the allyl silane which can be used in the reaction include allyltrialkylsilane, allyltriarylsilane and the like.
Examples of the Lewis acid which can be used in the reaction include titanium tetrachloride and the like.
Examples of the solvent which can be used in the reaction include diethyl ether, tetrahydrofuran, dioxane or the like ether solvent and hexane, pentane, benzene, toluene, xylene or the like hydrocarbon solvent, or a mixed solvent thereof. In this connection, when an allyl tin compound is used, water or a hydrous ether solvent may also be used.
The reaction temperature may be generally within the range of from xe2x88x9278 to 100xc2x0 C., preferably within the range of from xe2x88x9278 to 70xc2x0 C.
The reaction period may be generally within the range of from 5 minutes to 120 hours, preferably within the range of from 30 minutes to 48 hours.
Protection Reaction of Hydroxyl Group
The hydroxyl group of compound (VI) can be protected with a protective group generally used in this field.
Examples of the protective group include methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether or the like substituted methyl ether based protective group, 1-methoxyethyl ether, 2,2,2-trichloroethyl ether or the like substituted ethyl ether based protective group, benzyl ether, p-methoxybenzyl ether or the like substituted benzyl ether based protective group, triethylsilyl, t-butyldimethylsilyl or the like silyl ether based protective group, acetyl or the like ester based protective group and methoxycarbonyl, 2,2,2-trichloroethoxycarbonyl or the like carbonate based protective group.
Oxidation Reaction
In order to obtain the compound (VIII) from the compound (VII), a method generally used in this field may be employed, but the compound (VIII) can be obtained, for example, by subjecting the starting compound to a stoichiometric oxidation using osmium tetroxide or the like oxidizing agent or a catalytic oxidation reaction using a co-oxidizing agent, thereby once passing through diol, and then subjecting it to a general oxidation reaction such as periodic acid decomposition. Alternatively, the compound (VIII) can also be obtained by subjecting the compound (VII) to a general ozone decomposition accompanied by a reductive treatment in a solvent.
Examples of the oxidizing agent which can be used in the diol formation reaction include potassium permanganate, osmium tetroxide and the like, and examples of the co-oxidizing agent include hydrogen peroxide, hydrogen peroxide aqueous solution, perchloric acid, sodium perchloride and the like perchlorates, N-methylmorpholine-N-oxide, potassium hexacyanoferrate(III) and the like.
Examples of the solvent which can be used in the diol formation reaction include methanol, ethanol, t-butanol or the like alcohol solvent, acetone, methyl ethyl ketone or the like ketone solvent, dichloromethane, dichloroethane or the like chlorine based solvent, diethyl ether, tetrahydrofuran, dioxane or the like ether solvent, hexane, pentane, benzene or the like hydrocarbon solvent or water, and a mixed solvent thereof. The reaction temperature for diol formation may be generally within the range of from xe2x88x9278 to 100xc2x0 C., preferably within the range of from xe2x88x9278xc2x0 C. to room temperature. The reaction period may be generally within the range of from 5 minutes to 120 hours, preferably within the range of from 30 minutes to 48 hours.
The periodic acid decomposition of diol can be carried out using periodic acid, a periodate or the like as the oxidizing agent in a solvent such as methanol, ethanol, t-butanol or the like alcohol solvent, acetone, methyl ethyl ketone or the like ketone solvent, dichloromethane, dichloroethane or the like chlorine based solvent, diethyl ether, tetrahydrofuran, dioxane or the like ether solvent, hexane, pentane, benzene or the like hydrocarbon solvent or water, or a mixed solvent thereof.
The reaction temperature for periodic acid decomposition may be generally within the range of from xe2x88x9220 to 100xc2x0 C., preferably within the range of from 0xc2x0 C. to room temperature.
The reaction period may be generally within the range of from 5 minutes to 120 hours, preferably within the range of from 30 minutes to 48 hours.
Examples of the solvent which can be used in the ozone decomposition include methanol, ethanol, propanol or the like alcohol solvent, acetone, methyl ethyl ketone or the like ketone solvent, dichloromethane, dichloroethane or the like chlorine based solvent, diethyl ether, tetrahydrofuran, dioxane or the like ether solvent, hexane, pentane or the like hydrocarbon solvent or a mixed solvent thereof.
The ozone decomposition may be carried out at a temperature generally within the range of from xe2x88x9278 to 100xc2x0 C., preferably within the range of from xe2x88x9278xc2x0 C. to room temperature. The reaction period may be generally within the range of from 5 minutes to 120 hours, preferably within the range of from 30 minutes to 48 hours.
Reductive Amination Reaction
In order to obtain the compound (X) from the compound (VIII), a method generally used in this field may be employed. For example, the compound (X) can be obtained by allowing the compound (VIII) to react with a basic compound H-G and then treating it with a reducing agent.
Examples of the reducing agent which can be used include lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride or the like complex hydrogen compound and diborane, or hydrogenation in the presence of Raney nickel, palladium-carbon or the like catalyst may be employed. Examples of the solvent which can be used include methanol, ethanol, propanol or the like alcohol solvent, diethyl ether, tetrahydrofuran, dioxane or the like ether solvent, hexane, pentane, benzene, toluene, xylene or the like hydrocarbon solvent or a mixed solvent thereof.
The reductive amination reaction may be carried out at a temperature generally within the range of from xe2x88x9278 to 100xc2x0 C., preferably within the range of from xe2x88x9210xc2x0 C. to room temperature.
The reaction period may be generally within the range of from 5 minutes to 120 hours, preferably within the range of from 30 minutes to 48 hours.
Reduction Reaction
A compound (IX) in which R5 is hydrogen atom can be obtained by reducing carbonyl group of the compound (VIII).
The reduction can be carried out by a method generally used in this field. For example, a method in which the compound is treated in the presence of a reducing agent or a method in which hydrogenation is carried out in the presence of a catalyst can be used.
Examples of the reducing agent include borohydride compound and aluminum hydride compound. For example, sodium borohydride, lithium aluminum hydride and the like can be exemplified. Also, palladium, Raney nickel, platinum oxide and the like can be exemplified as the catalyst.
A solvent may be used in this reaction by optionally selecting it corresponding to the reducing agent, and its examples include methanol, ethanol, propanol or the like alcohol solvent, N,N-dimethylformamide, acetamide, dimethylacetamide or the like amide solvent, chloroform, dichloromethane, carbon tetrachloride or the like chlorine based solvent, diethyl ether, tetrahydrofuran, dioxane or the like ether solvent, hexane, pentane, benzene, toluene, xylene or the like hydrocarbon solvent or a mixed solvent thereof.
The reaction temperature may be generally within the range of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably within the range of from xe2x88x9278xc2x0 C. to room temperature.
The reaction period may be generally within the range of from 5 minutes to 120 hours, preferably within the range of from 30 minutes to 48 hours.
Addition Reaction of Alkyl Group
A compound (IX) in which R5 is other than hydrogen atom can be obtained by allowing the compound (VIII) to react with an alkyl metal compound.
The alkyl group addition reaction may be carried out by a method generally used in this field. For example, a method in which the compound is treated with an alkyl lithium, an alkylmagnesium halide or the like can be cited.
Examples of the alkyl metal compound include methyl lithium, ethyl lithium or the like alkyl lithium and methylmagnesium iodide, ethylmagnesium bromide or the like alkylmagnesium halide.
A solvent may be used in this reaction, and its examples include diethyl ether, tetrahydrofuran, dioxane or the like ether solvent, hexane, pentane, benzene, toluene, xylene or the like hydrocarbon solvent or a mixed solvent thereof.
The reaction temperature may be generally within the range of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably within the range of from xe2x88x9278xc2x0 C. to room temperature.
The reaction period may be generally within the range of from 5 minutes to 120 hours, preferably within the range of from 30 minutes to 48 hours.
Substitution Reaction of Amino Group
Corresponding compound (X) can be obtained by converting the hydroxyl group of compound (IX) into a halogen, sulfonic acid ester or the like leaving group and then subjecting it to substitution reaction with a basic compound H-G.
In order to convert the hydroxyl group into a halogen, sulfonic acid ester or the like leaving group, it may be carried out by a method generally used in this field. Examples of the halogenation method include a method in which the compound is treated with a phosphorus trihalide, a phosphorus pentahalide or the like in dichloromethane, chloroform or the like solvent and a method in which the compound is treated with a Vilsmeyer reagent such as N,N-dimethylchloroholminium chloride or bromide in N,N-dimethylformamide, dioxane or the like solvent. As the sulfonylation method, a method in which the compound is treated with methanesulfonyl chloride, p-toluenesulfonyl chloride or the like in a solvent in the presence of an appropriate base can be exemplified.
The substitution reaction of a derivative of the compound (IX) with the basic compound H-G can be carried out by a method generally used in this field. For example, a substituted compound (X) can be obtained by heating a mixture of the derivative of compound (IX) with basic compound H-G in acetonitrile or the like solvent in the presence of potassium carbonate or the like base.
Deprotection Reaction
The protective group of the hydroxyl group of compound (X) can be deprotected under a deprotection reaction condition generally used for the used protective group.
Dehydration Reaction
The compound (I) of interest can be obtained by dehydrating the compound (XI). The dehydration can be carried out by a method generally used in this field. For example, a method in which the compound is heated in the presence of an acid can be cited.
The acid which can be used may be either an organic acid or an inorganic acid. Hydrochloric acid, sulfuric acid, hydrobromic acid, potassium hydrogensulfate and the like can be exemplified as the inorganic acid, and p-toluenesulfonic acid, methanesulfonic acid, oxalic acid and the like can be exemplified as the organic acid. An inorganic acid is desirable as the acid. In addition to these, alumina can also be used.
A solvent may be used in this reaction, and its examples include N,N-dimethylformamide, acetamide, dimethylacetamide or the like amide solvent, chloroform, dichloromethane, carbon tetrachloride or the like halogenated hydrocarbon solvent, diethyl ether, tetrahydrofuran, dioxane or the like ether solvent and benzene, toluene, xylene or the like aromatic hydrocarbon solvent. A mixed solvent thereof may also be used.
The reaction temperature may be generally within the range of from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably within the range of from 0xc2x0 C. to 100xc2x0 C.
The reaction period may be generally within the range of from 5 minutes to 72 hours, preferably within the range of from 10 minutes to 24 hours.
In addition, a compound in which its alkenyl group moiety is in trans form can also be obtained by a method shown in the following. 
(X2 represents a trialkylphosphonium group, a dialkylphosphoryl group, a dialkylphosphono group or a trialkyl phosphoranylidene group, and R1, R2, R3, R4, R5, Q and G are as defined in the foregoing.)
That is, the compound (I) can be obtained by allowing the compound (IIa) to undergo Witting reaction with a compound (XII) and subjecting the thus obtained xcex1,xcex2 unsaturated carbonyl compound (XIII) to reductive amination reaction with a basic compound H-G. When the compound (XIII) is an xcex1,xcex2 unsaturated aldehyde (R5=H in the formula), it can also be obtained by allowing the compound (IIa) to undergo Witting reaction with a compound (XIIa), subjecting the thus obtained xcex1,xcex2 unsaturated carbonyl compound (XIIIa) to reduction reaction and then oxidizing the thus obtained compound (XIV). Also, it is possible to obtain the compound (I) by subjecting the compound (XIII) to reduction reaction, converting the hydroxyl group of the thus obtained compound (XIV) into a leaving group and then carrying out its substitution reaction with a basic compound H-G.
Each reaction step is described.
Witting Reaction
In order to obtain the compound (XIII) from the compound (IIa), it can be effected by carrying out a method generally used in this field. For example, the compound (XIII) can be obtained by treating the compound (IIa) with the compound (XII) in a solvent under a basic reaction condition or a neutral reaction condition.
Examples of the base include n-butyl lithium, phenyl lithium, sodium hydride, potassium t-butoxide, sodium ethoxide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
Examples of the solvent which can be used include diethyl ether, tetrahydrofuran, dioxane or the like ether solvent, benzene, toluene, xylene or the like aromatic hydrocarbon solvent, methanol, ethanol, propanol or the like alcohol solvent, N,N-dimethylformamide, acetamide, dimethylacetamide or the like amide solvent and chloroform, dichloromethane, carbon tetrachloride or the like halogenated hydrocarbon solvent. A mixed solvent thereof may also be used.
The reaction temperature may be generally within the range of from 30xc2x0 C. to 150xc2x0 C., preferably within the range of from 50xc2x0 C. to 100xc2x0 C.
The reaction period may be generally within the range of from 5 minutes to 72 hours, preferably within the range of from 10 minutes to 24 hours.
Reductive Amination Reaction
In order to obtain the compound (I) from the compound (XIII), a method generally used in this field may be employed. For example, the compound (I) can be obtained by allowing the compound (XIII) to react with a basic compound H-G and then treating it with a reducing agent.
Examples of the reducing agent which can be used include lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride or the like complex hydrogen compound. Examples of the solvent which can be used include methanol, ethanol, propanol or the like alcohol solvent, diethyl ether, tetrahydrofuran, dioxane or the like ether solvent, hexane, pentane, benzene, toluene, xylene or the like hydrocarbon solvent or a mixed solvent thereof.
The reductive amination reaction may be carried out at a temperature generally within the range of from xe2x88x9278 to 100xc2x0 C., preferably within the range of from xe2x88x9210xc2x0 C. to room temperature.
The reaction period may be generally within the range of from 5 minutes to 120 hours, preferably within the range of from 30 minutes to 48 hours.
Reduction Reaction
By reducing the carbonyl group of compound (XIII) or the ester group of compound (XIIIa), the corresponding alcohol (XIV) can be obtained. The reduction can be carried out by a method generally used in this field. For example, a method in which the compound is treated in the presence of a reducing agent can be employed.
Examples of the reducing agent include boron hydride compounds and aluminum hydride compounds. Preferably, diisobutylaluminum hydride can be used.
A solvent may be used in this reaction by optionally selecting it corresponding to the reducing agent, and its examples include methanol, ethanol, propanol or the like alcohol solvent, N,N-dimethylformamide, acetamide, dimethylacetamide or the like amide solvent, chloroform, dichloromethane, carbon tetrachloride or the like chlorine based solvent, diethyl ether, tetrahydrofuran, dioxane or the like ether solvent, hexane, pentane, benzene, toluene, xylene or the like hydrocarbon solvent or a mixed solvent thereof.
The reaction temperature may be generally within the range of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably within the range of from xe2x88x9278xc2x0 C. to room temperature.
The reaction period may be generally within the range of from 5 minutes to 120 hours, preferably within the range of from 30 minutes to 48 hours.
Oxidation Reaction
In older to obtain the compound (XIII) from the compound (XIV), it may be effected by carrying out a method generally used in this field. For example, a method in which the compound is treated in the presence of an oxidizing agent can be employed. As the oxidizing agent, silver oxide, lead tetracetate, a chrome based oxidizing agent, a manganese based oxidizing agent and the like can be used, and manganese dioxide can be preferably used.
A solvent may be used in this reaction by optionally selecting it corresponding to the reducing agent, and its examples include acetone, ethyl methyl ketone or the like ketone solvent, N,N-dimethylformamide, acetamide, dimethylacetamide or the like amide solvent, chloroform, dichloromethane, carbon tetrachloride or the like chlorine based solvent, diethyl ether, tetrahydrofuran, dioxane or the like ether solvent, hexane, pentane, benzene, toluene, xylene or the like hydrocarbon solvent, pyridine or the like basic solvent, acetic acid, phosphoric acid or the like acidic solvent or a mixed solvent thereof.
The reaction temperature may be generally within the range of from xe2x88x9278xc2x0 C. to 100xc2x0 C.
The reaction period may be generally within the range of from 5 minutes to 120 hours, preferably within the range of from 30 minutes to 48 hours.
Substitution Reaction of Amino Group
Corresponding complex (I) can be obtained by converting the hydroxyl group of compound (XIV) into a halogen, sulfonic acid ester or the like leaving group and then subjecting it to substitution reaction with a basic compound H-G.
In order to convert the hydroxyl group into a halogen, sulfonic acid ester or the like leaving group, it may be carried out by a method generally used in this field.
Examples of the halogenation method include a method in which the compound is treated with a phosphorus trihalide, a phosphorus pentahalide or the like in dichloromethane, chloroform or the like solvent, a method in which the compound is treated with hexachloroacetone or with carbon tetrachloride and triphenylphosphine in dichloromethane, chloroform or the like solvent and a method in which the compound is treated with a Vilsmeyer reagent such as N,N-dimethylchloroholminium chloride or bromide in N,N-dimethylformamide, dioxane or the like solvent.
As the sulfonylation method, a method in which the compound is treated with methanesulfonyl chloride, p-toluenesulfonyl chloride or the like in a solvent in the presence of an appropriate base can be exemplified.
The substitution reaction of a derivative of the compound (XIV) with the basic compound H-G can be carried out by a method generally used in this field. For example, the compound (I) can be obtained by heating a mixture of the derivative of compound (XIV) with basic compound H-G in acetonitrile or the like solvent in the presence of potassium carbonate or the like base.
As occasion demands, the compound of this invention can be made into a physiologically acceptable salt by converting it using hydrochloric acid, sulfuric acid, phosphoric acid or the like inorganic acid or formic acid, acetic acid, methanesulfonic acid or the like organic acid.
In addition, the free form or salt of the compound of this invention may exist as a hydrate.
The antitumor agent of this invention can be administered as various injections such as for intravenous injection, intramuscular injection and subcutaneous injection, or by oral administration and the like various methods. Among these administration methods, intravenous injection by an aqueous preparation and oral administration are desirable.
The aqueous preparation can be prepared by making the compound into an acid addition product with a pharmacologically acceptable acid. In the case of oral administration, the compound may be either its free form or salt form.
Regarding the preparation method of pharmaceutical preparations, they can be prepared by generally used various preparation methods of pharmaceutical preparations, by selecting an appropriate pharmaceutical preparation in response to each administration method.
Among dosage forms of the antitumor agent of this invention, tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions and the like can be exemplified as the oral preparations.
Regarding the injections, the preparation may contain stabilizers, antiseptics and solubilizing agents, and a solution which may contain these auxiliary agents may be made into a solid preparation by freeze-drying or the like means after putting it into a container, which is dissolved when used. Also, one dose may be contained in a container or multiple doses may be contained in the same container.
Solutions, suspensions, emulsions and the like can be exemplified as the liquid preparations, and a suspending agent, an emulsifying agent or the like can be used as an additive agent when these pharmaceutical preparations are prepared.
It is desirable that the antitumor agent containing the compound of this invention is administered as the compound once a day per adult, by repeating it at an appropriate interval. In addition, the dose is within the range of from 1 mg to 3 g, preferably within the range of from 5 mg to 2 g.
Next, antitumor effects of the compound of this invention obtained in the aforementioned manner are shown with reference to test examples.
Test Example 1
A human pulmonary carcinoma strain PC-12 which had been subcultured using RPMI 1640 containing 10% fetal calf serum, 2 mM of L-glutamine and 100 xcexcg/ml of kanamycin sulfate was inoculated into a 96 well microplate at an inoculum size of 1.0xc3x971.03 cells/150 xcexcl/well, and 50 xcexcl/well of a sample was added 24 hours thereafter. The cells were then cultured for 3 days, and a 5 mg/ml solution of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) was dispensed in 20 xcexcl/well portions. Four hours thereafter, the culture medium was discarded, dimethyl sulfoxide was dispensed in 150 xcexcl/well portions and the absorbance was measured at 540 nm. The antitumor effect was shown by GI50 value (ng/ml) as a drug concentration which reduced cell growth of the drug-added group to 50% of the control group.
As is evident from Table 1, the compounds synthesized in this invention showed antitumor activity, so that they can be used as antitumor agents for the treatment of various tumors.
Test Example 2
 less than Coordination Inhibition Test greater than 
Rotation speed of the rotary rod (3 cm in diameter) of RotaRod apparatus (mfd. by Natsume Seisaku-sho) was set to 10 rpm, and mice (Balb/c) which stood on the rod for 60 seconds or more were selected. After 1, 4 or 24 hours of the oral administration of each test sample, these mice were put on the rod, and the mice which dropped within 60 seconds were regarded as coordination inhibition action positive. The results are shown in Table 2.
Among these compounds, a compound typified by Example 22 of a previously applied patent (Japanese Patent Application No. 7-247096) showed strong coordination inhibition action by a single dose (10 mg of dose in the case of Example 22 of Japanese Patent Application No. 7-247096) at around the maximum tolerated dose expressing the antitumor action when orally administered to mice. On the other hand, a series of compounds disclosed by this invention showed completely no coordination inhibition action or extremely weak action at a dose showing the drug efficacy IR of 58% or more or by single administration at more larger dose.
Next, this invention is described further in detail with reference to examples (in structural formulae in the examples, Me means methyl group and Boc means t-butoxycarbonyl group).